| A Novel Acidic 11B-Hydroxysteroid Dehydrogenase Type 1 (11B-HSD1) Inhibitor with Reduced Acyl Glucuronide Liability: The Discovery of 4-[4-(2-Adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329). | |
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MedLine Citation:
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PMID: 23088558 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Inhibition of 11B-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimisation of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimsation of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability. |
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Authors:
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James S Scott; Joanne Deschoolmeester; Elaine Kilgour; Rachel M Mayers; Martin J Packer; David Hargreaves; Stefan Gerhardt; Derek J Ogg; Amanda Rees; Nidhal Selmi; Andrew Stocker; John G Swales; Paul R O Whittamore |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-10-22 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: - ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-23 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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